This Program Project Grant includes the commitment of four laboratories to the study of autoimmunity. All four of us, Emil Unanue, Osami Kanagawa, Paul Allen, and Kenneth Murphy have been studying the biology of T cells and of antigen presentation, and have contributed to our understanding of antigen processing, peptide interaction with MHC molecules and the molecular basis of T cell differentiation. Within our immunology faculty, the four of us form a small interest group studying the application of basic studies of T cell and MHC biology to immunopathology. Our interactions are promoted through joint meetings, shared facilities and exchange of ideas among our laboratory staff and trainees. Subproject 0005 contains the investigations of Uanue and Kanagawa on autoimmune diabetes in the NOD mouse. The major focus is the identification of diabetogenic antigens and the analysis of antigen presentation, having an emphasis on the antigens that incite the early autoantibody response. The investigations of Paul Allen on autoimmune arthritis using the KRN model are included in subproject 0008. The Allen laboratory has placed a strong emphasis on studying the molecular basis of how T cells recognize autoantigens. In this project, they apply their experience to the special situation of the KRN T cell that recognizes a self peptide of the G6PI protein. Included are studies on the mechanisms of entry of antibodies into the joint to cause disease. Ken Murphy identified a new gene when searching, in the last cycle of this PPG, for novel Th1 specific genes. Murphy has knockout mice that lack the new gene and has early provocative evidence that the protein may have a negative regulatory role. For example, mice lacking the gene have a heightened incidence of experimental allergic encephalomyelitis. Murphy proposes a range of molecular and biological researches on this novel protein, including examining its role in a series of autoimmunities.